Anthelmintic methods of use

ABSTRACT

The thioallophanate compound represented by the following general formula ##EQU1## wherein X is hydrogen, chlorine atom, nitro or methyl group: Z is a substituting group selected from the group consisting of ##EQU2## and ##EQU3## has excellent anthelmintic activity and can be used for controlling helminthiasis of animals.

DETAILED EXPLANATION OF THE INVENTION

This invention relates to compositions useful against helminthiasis and more particularly concerns anthelmintic compositions containing thioallophanate as ingredient.

Helminthiasis, the infestation of the body of domestic animals such as sheep, cattle, horses, goats, pigs, poultry, dogs and cats, by various species of parasitic worms, is perhaps the most common, most serious and most widespread disease in the world. Although the economic significance of this disease has led to extensive research for new and more effective anthelmintics, most of countermeasures developed to date have not been entirely satisfactory for one or more reasons; e.g. poor therapeutic index, specificity of action, high cost, low activity, limited anthelmintic spectrum.

According to this invention, it has been found that the specific thioallophanate compounds herein described possess a significant anthelmintic activity and can be effectively employed in the treatment and/or prevention of helminthiasis.

It is one object of the present invention to provide compositions containing such substances as an active anthelmintic ingredient. It is an additional object to provide methods of using them for the purpose of controlling helminthiasis. Further objects of the invention will become apparent from the following discussion of the invention.

According to the present invention, it has been surprisingly discovered that the thioallophanate compound represented by the following general formula (1) has excellent anthelmintic activity: ##EQU4## wherein X is hydrogen, chlorine atom, nitro or methyl group: Z is a substituting group selected from the group consisting of ##EQU5## and ##EQU6## R₁ represents hydrogen atom or methyl group: R₂ represents alkyl having not more than 12 carbon atoms, alkyl having not more than 3 carbon atoms substituted with halogen, methoxy or phenyl group, alkenyl having 3 carbon atoms which may be substituted with halogen atom, methoxy or phenyl group, alkynyl having 3 carbon atoms and aryl having not more than 10 carbon atoms which may be substituted with halogen atom, nitro or methyl group: R₃ and R₄ represent hydrogen atom or lower alkyl group respectively: R₅ represents hydrogen atom, alkyl or cycloalkyl having not more than 4 carbon atoms, phenyl, alkoxy having not more than 4 carbon atoms, amino, alkylamino, 3,3-dimethyl-2-thioureido or 3,3-dimethylureido group: R₆ and R₇ represent hydrogen and chlorine atoms, methoxy, methyl or nitro group respectively: A represents inorganic acid or organic acid which is capable of forming a salt with an amino group: Y represents oxygen or sulfur atom: and n represents an integer of 0 - 3.

These compound can be prepared according to conventional processes. For example, the production process for the compound in which Z is ##EQU7## group was disclosed in the Patentblatt of German Pat. No. 1806123.9 issued on June 4, 1969 and the production process of other compounds were disclosed in the Patentblatt of German Pat. No. 1,930,540.9 issued on Jan. 8, 1970.

Typical examples of the thioallophanates which can be used in the present invention are listed in the Table 1.

                                                           Melting                                                                        Point or                No. of                                                 Decomposion             Compound                                                                             Structural Formula               Chemical Name   Point (d)                                                                      (°C)             __________________________________________________________________________           SO                                                                             ∥∥             2-(3-Methoxycarbonyl-2-                 1     C--NH--C--O--CH.sub.3            thioureido)-aniline                                                                            184-185(d)                    SO                                                                             ∥∥             2-(3-Ethoxycarbonyl-2-                  2     C--NH--C--O--C.sub.2 H.sub.5     thioureido)-aniline                                                                            162-162.5(d)                  SO                                                                             ∥∥CH.sub.3     2-(3-iso-Propoxy-                             C--NH--C--O--CH∠           carbonyl-2-thioureido)                                                                         137-138                 3     CH.sub.3                         aniline                                       SO                               1-(2-Amino-4-methyl-                          ∥∥             phenyl)-3-methoxy-                                                                             167.5-168.5(d)          4     C--NH--C--O--CH.sub.3            carbonyl-2-thiourea                           SO                               1-(2-Amino-5-chlorophenyl)-                   ∥∥             3-methoxycarbonyl-2-                                                                           182-182.5(d)                  NH--C--NH--C--O--C.sub.2 H.sub.5 thiourea                                      NH.sub.2                                                                       SO                               1-(2-Amino-5-nitrophenyl)-                    ∥∥             3-methoxycarbonyl-2-                                                                           202-203(d)              6     NH--C--NH--C--O--C.sub.2 H.sub.5 thiourea                                      NH.sub.2                                                                       SO                                                                             ∥∥             2-(3-Methoxycarbonyl-2-                       NH--C--NH--C--O--CH.sub.3        thioureido)-aniline                                                                            153(d)e                       NH.sub.2.HNO.sub.3                                                             SO                                                                             ∥∥                                                           NH--C--NH--C--O--CH.sub.3        2-(3-Methoxycarbonyl-2-                 8     NH.sub.2.COOH                    thioureido)-aniline                                                                            151.5-152(d)                  |                                                                     COOH                                                                           SO                               2-(3-Ethoxycarboyl-2-                         ∥∥             thioureido)-aniline                                                                            188(d)                  9     NH--C--NH--C--O--C.sub.2 H.sub.5 hydrochloride                                 NH.sub.2.HCl                                                                   SO                                                                             ∥∥             2-(3-Ethoxycarbonyl-2-                  10    NH--C--NH--C--O--C.sub.2 H.sub.5 thioureido)-aniline                                                                            140.2-140.3(d)                SO                               2-(3-Ethoxycarbonyl-                          ∥∥             2-thioureido)-aniline                                                                          140(d)                  11    NH--C--NH--C--O--C.sub.2 H.sub.5 oxalate                                       SO                               2-(3-Ethoxycarbonyl-                          ∥∥             2-thioureido)-aniline                                                                          174(d)                  12    NH--C--NH--C--O--C.sub.2 H.sub.5 para-toluenesulfonate                         SO                               2-(3-Ethoxycarbonyl-                          ∥∥             2-thioureido)-N-methyl-                                                                        171                     13    C-- NH--C--O--C.sub.2 H.sub.5    aniline                                       SO                               2-(3-Ethoxycarbonyl-                          ∥∥             2-thioureido)-N,N-                                                                             111-113                 14    NH--C--NH--C--O--C.sub.2 H.sub.5 dimethylaniline                               CH.sub.3                                                                       N∠                                                                       CH.sub.3                                                                       SO                               2-(3-Ethoxycarbonyl-2-                        ∥∥             thioureido)-N,N-di-                                                                            167-168)d)              15    CH.sub.3                         methylaniline hydrochloride                   N∠. HCl                                                                  CH.sub.3                                                                       S                                1-(3-Ethoxycarbonyl-2-                        ∥                       thioureido)2-N,N-dimethyl-                                                                     170-171                       NHCNHCOOC.sub.2 H.sub.5          aminobenzene oxalate                    16    CH.sub.3 COOH                                                                  N∠. |                                                           CH.sub.3 COOH                                                                  SO                                                                             ∥∥             1-Formamido-2-(3-                             NH--C--NH--C--O--CH.sub.3        methoxycarbonyl-2-                                                                             185(d)                  17                                     thioureido)-benzene                           NH--C--H                                                                       ∥                                                                     O                                                                              SO                                                                             ∥∥             1-Acetamido-2-(3-                             NH--C--NH--C--O--CH.sub.3        methoxycarbonyl-2-                                                                             192.5-193.5             18                                     thioureido)-benzene                           NH--C--CH.sub.3                                                                ∥                                                                     O                                                                              SO                                                                             ∥∥             1-Propionamido-2-(3-                          NH--C--NH--C--O-- C.sub.2 H.sub.5                                                                               ethoxycarbonyl-2-                                                                              170-171.5               19                                     thioureido)-benzene                           NH--C--C.sub.2 H.sub.5                                                         ∥                                                                     O                                                                                                               1-Cyclopropancarbonamido-               20                                     2-(3-methoxycarbonyl-2-                                                                        191-192(d)                                                     thioureido)-benzene                                                            1-Benzamido-2-(3-                       21                                     ethoxycarbonyl-2-                                                                              192-193                                                        thioureido)-benzene                           SO                                                                             ∥∥             1-Methoxycarbonamido-2-                       NH--C--NH--C--O--C.sub.2 H.sub.5 (3-ethoxycarbonyl-2-                                                                           168-170(d)              22                                     thioureido)-benzene                           NH--C--O--CH.sub.3                                                             ∥                                                                     O                                                                              SO                                                                             ∥∥             1-Ethoxycarbonamido-2-                        NH--C--NH--C--O--CH.sub.3        (3-methoxycarbonyl-2-                                                                          147-149(d)              23                                     thioureido)-benzene                           NH--C--O--C.sub.2 H.sub.5                                                      ∥                                                                     O                                                                              SO                                                                             ∥∥             1-(3-n-Propylureido)-2-                       NH--C--NH--C--O--CH.sub.3        (3-methoxycarbonyl-2-                                                                          132.5-133.5             24                                     thioureido)-benzene                           NH--C--NH--C.sub.3 H.sub.7                                                     ∥                                                                     O                                                                              SO                                                                             ∥∥             1-(3-n-Butylureido)-2-                        NH--C-- NH--C--O--CH.sub.3       (3-methoxycarbonyl-2-                                                                          182-183                 25                                     thioureido)-benzene                           NH--C--NH--C.sub.4 H.sub.9                                                     ∥                                                                     O                                                                              SO                                                                             ∥∥             1-(3-n-Butylureido)-2-                        NH--C--NH--C--O--C.sub.2 H.sub.5 (3-ethoxycarbonyl-2-                                                                           182                     26                                     thioureido)-benzene                           NH--C--NH--C.sub.4 H.sub.9                                                     ∥                                                                     O                                                                              SO                                                                             ∥∥             1-Thioformamido-2-(3-                         NH--C--NH--C--O--C.sub.2 H.sub.5 ethoxycarbonyl-2-                                                                              172                     27                                     thioureido)-benzene                           NH--C--H                                                                       ∥                                                                     O                                                                              SO                                                                             ∥∥             1-(2-Thiocarbamoyl-                           NH--C--NH--C--O--C.sub.2 H.sub.5 aminophenyl)-3-ethoxy-                                                                         157(d)                  28                                     carbonylthiourea                              NH--C--NH.sub.2                                                                ∥                                                                     S                                                                              SO                                                                             ∥∥             1-(3-Ethoxycarbonyl-2-                        NH--C--NH--C--O--C.sub.2 H.sub.5 thioureido)-2-(3-methyl-                                                                       160-161                 29                                     2-thioureido)-benzene                         NH--C--NH--CH.sub.3                                                            ∥                                                                     S                                                                              SO                                                                             ∥∥             1-(3-n-Propyl-2-thioureido)-                  NH--C--NH--C--O--C.sub.2 H.sub.5 2-(3-ethoxycarbonyl-2-                                                                         132.5-133.5(d)          30                                     thioureido)-benzene                           NH--C--NH--C.sub.3 H.sub.7                                                     ∥                                                                     S                                                                              S                                1-(3-N,N-Dimethylamino-2-                     ∥                       thiocarbonyl-2-thioureido)-                   NHCNHCOOCH.sub.3                 2-(3-methoxycarbonyl-2-                                                                        149(d)                  31    CH.sub.3                         thioureido)-benzene                           NHCNH--C--N∠                                                             ∥∥CH.sub.3                                                   SS                                                                             SO                                                                             ∥∥             1-(3-N,N-Dimethylaminothio-                   NH--C--NH--C--O--C.sub.2 H.sub.5 carbonyl-2-thioureido)-2-               32    CH.sub.3                         (3-ethoxycarbonyl-2-                                                                           148-149(d)                    NH--C--NH--C--N∠           thioureido)-benzene                           ∥∥CH.sub.3                                                   SS                                                                             SO                               1-(3-N,N-Dimethylamino-                       ∥∥             carbonyl-2-thioureido)-                       NH--C--NH--C--O--CH.sub.3        2-(3-methoxycarbonyl-2-                                                                        159-160(d)              33    CH.sub.3                         thioureido)-benzene                           NH--C--NH--C--N∠                                                         ∥∥CH.sub.3                                                   SO                                                                                                              1-Benzylidenamino-2-                    34                                     (3-methoxycarbonyl-2-                                                                          145-146                                                        thioureido)-benzene                                                            1-(4-Chlorobenzylidenamino)-            35                                     2-(3-methoxycarbonyl-2-                                                                        183-183.5(d)                                                   thioureido)-benzene                                                            1-(4-Methoxybenzyliden-                 36                                     amino)-2-(3-methoxycarbonyl-                                                                   159-159.5(d)                                                   2-thioureido)-benzene                                                          1-(3-Nitrobenzyliden-                   37                                     amino-2-(3-ethoxycarbonyl-                                                                     185(d)                                                         2-thioureido)-benzene                                                          1-Benzenesulfonicamido-2-               38                                     (3-methoxycarbonyl-2-                                                                          197-198(d)                                                     thioureido)-benzene                                                            1-(4-Toluenesulfonicamido)-             39                                     2-(3-ethoxycarbonyl-2-                                                                         179-180(d)                                                     thioureido)-benzene                                                            1-(4-Chlorobenzenesulfonic-             40                                     amodo)-2-(3-methoxycarbonyl-                                                                   192-193(d)                                                     2-thioureido)-benzene                         S                                                                              ∥                       2(3-Allyloxycarbonyl-2-                 41    CNHCOOCH.sub.2 CH=CH.sub.3       thioureido)-aniline                                                                            138-139                       SO                                                                             ∥∥                                                           NH--C--NH--C--O--CH.sub.3        1,2-Bis(3-methoxycarbonyl-              42                                     2-thioureido)-benzene                                                                          181.5-182.5(d)                                                                 - NH--C--NH--C--O--                                                            CH.sub.3                      ∥∥                                                           SO                                                                             SO                                                                             ∥∥                                                           NH--C--NH--C--O--C.sub.2 H.sub.5 1,2-Bis(3-ethoxycarbonyl-               43                                     2-thioureido)-benzene                                                                          195(d)                        NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                            SO                                                                            SO                                                                             ∥∥             1,2-Bis(3-isopropoxy-                         NH--C--NH--C--O--CH(CH.sub.3).sub.2                                                                             carbonyl-2-thioureido)-                                                                        205-206(d)              44                                     benzene                                       NH--C--NH--C--O--CH(CH.sub.3).sub.2                                            ∥∥                                                           SO                                                                             SO                                                                             ∥∥                                                           NH--C--NH--C--O--CH.sub.2 CH(CH.sub.3).sub.2                                                                    1,2-Bis(3-isobutoxycarbonyl-            45                                     2-thioureido)-benzene                                                                          197-198(d)                    NH--C--NH--C--O--CH.sub.2 CH(CH.sub.3).sub.2                                   ∥∥                                                           SO                                                                             SO                                                                             ∥∥             3,4-Bis(3-ethoxycarbonyl-                     NH--C--NH--C--O--C.sub.2 H.sub.5 2-thioureido) toluene                                                                          175-176(d)              46                                                                                   NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis(3-ethoxycarbonyl-                     NH--C--NH--C--O--C.sub.2 H.sub.5 2-thioureido)-4-                                                                               170.5-171.5(d)          47                                     chlorobenzene                                 NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis(3-ethoxycarbonyl-                     NH--C--NH--C--O--C.sub.2 H.sub.5 2-thioureido)-4-                                                                               205-205.5(d)            48                                     nitrobenzene                                  NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis(3-ethoxycarbonyl-                     NH--C--NH--C--O--C.sub.2 H.sub.5 2-thioureido)-4.5-                                                                             206-207(d)              49                                     dichlorobenzene                               NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis(3-ethoxycarbonyl-                     NH--C--NH--C--O--C.sub.2 H.sub.5 2-thioureido)-3,4,6-                                                                           180-181                 50                                     trichlorobenzen                               NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis(3-benzyloxy-                          NH--C--NH--C--O--CH.sub.2        carbonyl-2-thioureido)-                                                                        171-172                 51                                     benzene                                       NH--C--NH--C--O--CH.sub.2                                                      ∥∥                                                           SO                                                                             SO                                                                              ∥∥            1,2-Bis[3-(-β-Methoxy)                   NH--C--NH--C--O--CH.sub.2 CH.sub.2 OCH.sub.3                                                                    ethoxycarbonyl-2-thioureido]                                                                   170.5-171.5             52                                     benzene                                       NH--C--NH--C--O--CH.sub.2 CH.sub.2 OCH.sub.3                                   ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-(β-chloroethoxy-               NH--C--NH--C--C--C.sub.2 H.sub.4 Cl                                                                             carbonyl)-2-thioureido]                                                                        181-182(d)              53                                     benzene                                       NH--C--NH--C--O--C.sub.2 H.sub.4 Cl                                            ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[(3-ethylthio)-                        NH--C--NH--C--S--C.sub.2 H.sub.5 carbonyl-2-thioureido]                                                                         191-192(d)              54                                     benzene                                       NH--C--NH--C--S--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-dodecylthio)                        NH--C--NH--C--S--n-C.sub.12 H.sub.25                                                                            carbonyl]-thioureido-                                                                          122-123.5(d)            55                                     benzene                                       NH--C--NH--C--S--n-C.sub.12 H.sub.25                                           ∥∥                                                           SO                                                                             SO                                                                             ∥∥                                                           NH--C--NH--C--O--CH.sub.2 CH=CH.sub.2                                                                           1,2-Bis(3-allyloxycarbonyl-             56                                     2-thioureido) benzene                                                                          166-167                       NH--C--NH--C--O--CH.sub.2 CH=CH.sub.2                                          ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-(2-Propynyloxy-                     NH--C--NH--C--O--CH.sub.2 --C.tbd.CH                                                                            carbonyl)-2-thioureido]                                                                        172-173(d)              57                                     benzene                                       NH--C--NH--C--O--CH.sub.2 --C.tbd.CH                                           ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-(4-chlorophenoxy-                   NH--C--NH--C--O                  carbonyl)-2-thioureido]                                                                        193(d)                  58                                     benzene                                       NH--C--NH--C--O                                                                ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-(4-nitrophenoxy-                    NH--C--NH--C--O                  carbonyl)-2-thioureido]                                                                        186(d)                  59                                     benzene                                       NH--C--NH--C--O                                                                ∥∥                                                           SO                                                                             SO                                                                             ∥∥                                                           NH--C--NH--C--O                  1,2-Bis[3-(4-methylphenoxy-             60                                     carbonyl)-2-thioureido]-                                                                       191-192(d)                    NH--C--NH--C--O                  4-chlorobenzene                               ∥∥                                                           SO                                                                             SO                                                                             ∥∥                                                           NH--C--NH--C--O--                3,4-Bis[3-(4-chlorophenoxy-             61                                     carbonyl)-2-thioureido]-                                                                       199-200(d)                    NH--C--NH--C--O--                toluene                                       ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-(2-naphthoxy-                       NH--C--NH--C--O                  carbonyl)-2-thioureido]                                                                        191-192(d)              62                                     benzene                                       NH--C--NH--C--O                                                                ∥∥                                                           SO                                                                             SO                                                                             ∥∥             1,2-Bis[3-(2-naphthoxy-                       NH--O--NH--C--O                  carbonyl)-2-thioureido]                                                                        180(d)                  63                                                                             4'-nitrobenzene                                                                      NH--O--NH--C--O                                                                ∥∥                                                           SO                                                                                                              1-(3-Ethoxycarbonyl-2-                                                         throureido)-2-(3-ethoxy-                64                                     carbonyl-1-methyl-2-                                                                           176-177(d)                                                     throureido)-benzene                                                            1,2-Bis(3-ethoxycarbonyl-1-             65                                     methyl-2-thioureido)benzene                   SO                               1-(3-Ethoxycarbonyl-2-                        ∥∥             thioureido)-2-(3-methoxy-                     NH--C--NH--C--O--CH.sub.3        carbonyl-2-thioureido)-                                                                        177-178(d)              66                                     benzene                                       NH--C--NH--C--O--C.sub.2 H.sub.5                                               ∥∥                                                           SO                                                                       __________________________________________________________________________      note: Symbol (d) means decomposition                                     

The above compound may be used in connection with any carrier vehicle and in the form of a solution, capsule, tablet or bolus.

Among the compounds employed as an ingredient of this invention, the salts (e.g. compound 7 ˜ 12, 15, 16) have high solubility in water and then they can be added to the drinking water just before use, or a drench formulation can be prepared in advance which may be diluted up to the desired concentration. When the composition of the present invention is in the form of solution, liquid media, e.g. alcohols, acetone, dimethyl sulfoxide, dimethylformamide, dioxane and cyclohexanone can be used. In the drench or solution preparation, concentrations may be 10% - 40% wt/vol. The exact percentage used will depend upon the dosage level required and the limitation imposed on the volume to be administered.

When administered in powdered form, the anthelmintic ingredient may be dispersed in or admixed with standard elements of animal sustenance, such as feed, or other orally ingestible carriers, such as distiller's dried grains, corn meal, alfalfa, ground oyster shells, molasses solubles, or corn cob meal. This method is generally used when it is desired to administer the compounds either as therapeutic or prophylactic use over an extended period.

When the composition is used in the solid dosage forms such as a capsule, tablet, or bolus, the ingredient may be conveniently mixed with any other acceptable vehicles including diluents, fillers, binders and lubricants in the preparation of such forms, and preferably materials nutritionally suitable such as starch, lactose, magnesium stearate, vegetable gums, hydroxy alkyl cellulose and the like.

The proportion of the anthelmintic ingredients in the above forms of administration may vary widely depending upon the desired dosage sought to be administered to the infected host. Thus, tablets and boluses, whether enteric in nature or not, can incorporate, for example, in the ranges from 5%, to 80% of the anthelmintic ingredient by weight of the total composition. Although the dosage rate varies depending on the mode of treatment, the activity of the components, the size of the host and the severity of infection, when single unit dosage forms such as tablets, boluses, or drenches are desired to be administered to the animal, suitable results are obtained when the compositions contain enough of the anthelmintic ingredients of the present invention to provide a dosage level of from 0.1 ˜ 1000 and preferably 5 ˜ 500mg/Kg of animal body weight.

If desired, the course of treatment may be extended over a period of days in which case the optimum daily dose level is reduced.

The following examples are given for the purpose of illustration only.

EXAMPLE 1

A bolus having the following composition suitable for oral administration was prepared.

    ______________________________________                                         Compound (I)     10       parts by weight                                      Dicalcium phosphate                                                                             3        "                                                    Starch           1.5      "                                                    Gum              0.3      "                                                    Talc             1        "                                                    Mg stearate      0.1      "                                                    ______________________________________                                    

The dicalcium phosphate was thoroughly mixed with the compound I and the mixture was pulverized to a particle size of less than 90 mesh. 1 part of starch was added to the mixture in the form of an aqueous starch paste and the resulting mixture was granulated in the usual manner. The granules were dried at 50°C. The guar gum and the balance of the starch were added and the mixture thoroughly blended. The remainder of the ingredients were then added and the whole completely mixed and compressed.

EXAMPLE 2.

A drench having the following composition

    Compound 2       10       parts by weight                                      Polyoxyethylene                                                                alkylphenol ether                                                                               0.1      "                                                    Silicone oil     0.02     "                                                    Starch           15.0     "                                               

was prepared by blending the ingredients into dry mix and the resulting mixture was added to 300ml. of water gradually.

EXAMPLE 3.

A drench having the following composition was prepared by usual formulating methods.

    ______________________________________                                         Compound 4       10       parts by weight                                      Silicone oil     0.02     "                                                    Hydroxy propyl                                                                 cellulose        1.2      "                                                    Water            150      "                                                    ______________________________________                                    

EXAMPLE 4.

Tablets having the following composition were prepared by the conventional process.

    ______________________________________                                         Compound 25      10       parts by weight                                      Calcium phosphate                                                                               8        "                                                    Hydroxypropyl                                                                  cellulose        1.5      "                                                    Lactose          80       "                                                    ______________________________________                                    

Hydroxypropylcellulose was dissolved into alcohol and the resulting solution was sprayed to the dry mix of the ingredients. After removing the solvent, the mixture was granulated in the usual manner and compressed to tablets having 0.2g of weight.

EXAMPLE 5.

Feed supplements according to the following compositions were prepared by the conventional process.

    ______________________________________                                         (1)  Compound 12     15                                                             Exoleated soybean                                                                              85                                                        (2)  Compound 42      5                                                             Wheat bran      95                                                        (3)  Compound 43     10                                                             Rice bran       90                                                        (4)  Compound 44     25                                                             Corn grain      75                                                        ______________________________________                                    

EXAMPLE 6.

50 parts of compound 66 was mixed with 50 parts of tricalcium phosphate. Then the resulting powder was subdivided and loaded into hard gelatin capsules in such a manner that each capsule contains the equivalent of 200mg of the active ingredient.

EXAMPLE 7.

The anthelmintic ingredients listed in Table 2 were mixed with the dog food consisting of imitation meat. The dogs naturally infected with toxocara canis were divided into groups consisting of three dogs and after checking the number of eggs in 1g of excrement of each dog, the above food was fed in such manner that the each dog received 50mg of the anthelmintic ingredient/Kg of body weight/day for 3 days. Egg counts were made on the third day following the last treatment. Results are tabulated below in Table 2.

                  Table 2                                                          ______________________________________                                                        Eggs (average)                                                  Compound                                                                               Dosage       Before      After                                                              Medication  Medication                                    ______________________________________                                         1       50mg/Kg/day  3,960        0                                            2       "            4,110        0                                            4       "            4,120       160                                           8       "            3,780        0                                            9       "            3,900        0                                            13      "            4,100       175                                           16      "            3,970       205                                           17      "            4,250        0                                            18      "            4,080        35                                           20      "            3,890        5                                            21      "            4,040       125                                           22      "            3,770        10                                           25      "            3,810        50                                           27      "            4,200        35                                           29      "            4,190       145                                           30      "            3,920       210                                           31      "            3,750       190                                           33      "            4,150       205                                           34      "            4,130       180                                           35      "            3,920        75                                           36      "            4,030        65                                           38      "            4,050        5                                            39      "            3,860        0                                            41      "            4,260        55                                           42      "            5,200       175                                           43      "            4,850        0                                            56      "            5,150       185                                           66      "            4,920       155                                           Piperazine                                                                             200mg/Kg/day 4,780       535                                           Control None         4,860       4,800                                         ______________________________________                                    

No secondary effect or change on excrement, blood and appetite was observed.

EXAMPLE 8.

Oral administration of the anthelmintic ingredients as a drench according to the composition of Example 2 to sheep which were naturally infected with gastrointeslinal nematodes was performed for three days at levels of 50mg of the anthelmintic ingredient /Kg of body weight/day. A dose of the same ingredients was given to a group consisting of three sheep and the results of the egg count before and after third day of treatment are tabulated below in Table 3.

                  Table 3                                                          ______________________________________                                                        Eggs (average)                                                  Compound                                                                               Dosage       Before      After                                                              Medication  Medication                                    ______________________________________                                         1       50mg/Kg/day  2,410        0                                            2       "            2,940        0                                            3       "            2,500       120                                           5       "            2,050        80                                           6       "            2,420       105                                           7       "            2,770        40                                           8       "            2,490        0                                            9       "            2,130        0                                            10      "            2,640        0                                            11      "            2,280        0                                            12      "            1,960       125                                           13      "            2,500       140                                           14      "            3,450        75                                           15      "            2,750       160                                           17      "            2,120        0                                            18      "            2,850        80                                           19      "            1,970       105                                           22      "            2,300        55                                           23      "            2,570       115                                           24      "            1,980       180                                           25      "            3,080        70                                           26      "            1,910        0                                            27      "            2,570        40                                           28      "            3,110        75                                           29      "            2,640       205                                           30      "            2,530        0                                            34      "            2,010       160                                           37      "            2,530        0                                            40      "            2,900        0                                            41      "            2,370        60                                           42      "            2,470        0                                            43      "            1,990        0                                            44      "            3,250       115                                           45      "            2,400       180                                           46      "            2,540       120                                           48      "            1,900        45                                           49      "            2,690       160                                           50      "            2,540       125                                           51      "            3,080        80                                           52      "            2,130        55                                           53      "            2,440        0                                            54      "            1,970       190                                           55      "            2,750       180                                           56      "            3,100       125                                           57      "            2,500       100                                           58      "            2,200        0                                            59      "            2,450        85                                           60      "            1,910        0                                            61      "            2,760        0                                            62      "            2,070       190                                           63      "            2,430        90                                           64      "            3,400       125                                           65      "            2,290        40                                           66      "            2,850        0                                            Control None         2,280       2310                                          "       None         3,250       3010                                          "       None         2,890       2960                                          ______________________________________                                    

No secondary effect or change on excrement, blood and appetite was observed. 

What is claimed is:
 1. A method for the treatment of helminth infections in man and domestic animals which comprises administering to man or a domestic animal infected with helminths an anthelmintically effective amount of a benzene derivative selected from the group consisting of:2-(3-ethoxycarbonyl-2-thioureido)-N,N-dimethylaniline, 2-(3-ethoxycarbonyl-2-thioureido)-N,N-dimethylaniline hydrochloride, 1-(3-ethoxycarbonyl-2-thioureido)2-N,N-dimethyl-amino-benzene oxalate, 1-formamido-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-acetamido-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-propionamido-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-cyclopropancarbonamido-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-benzamido-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-methoxycarbonamido-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-ethoxycarbonamido-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(3-n-propylureido)-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(3-n-butylureido)-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(3-n-butylureido)-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-thioformamido-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-(2-thiocarbamoyl-aminophenyl)-3-ethoxycarbonylthiourea, 1-(3-ethoxycarbonyl-2-thioureido)-2-(3-methyl-2-thioureido)-benzene, 1-(3-n-propyl-2-thioureido)-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-(3-N,N-dimethylamino-2-thiocarbonyl-2-thioureido)-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(3-N,N-dimethylaminothiocarbonyl-2-thioureido)-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-(3-N,N-dimethylamino-carbonyl-2-thioureido)-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-benzylidenamino-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(4-chlorobenzylidenamino)-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(4-methoxybenzylidenamino)-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(3-nitrobenzylidenamino-2-(3-ethoxycarbonyl-2-thioureido)-benzene, 1-benzenesulfonicamido-2-(3-methoxycarbonyl-2-thioureido)-benzene, 1-(4-toluenesulfonicamido)-2-(3-ethoxycarbonyl-2-thioureido)-benzene 1(4-chlorobenzenesulfonicamodo)-2-(3-methoxycarbonyl-2-thioureido)-benzene,
 1. 2-bis(3-benzyloxycarbonyl-2-thioureido)-benzene,1.2-bis[3-(β-methoxy) ethoxycarbonyl-2-thioureido]benzene, 1.2-bis]3-(β-chloroethoxycarbonyl)-2-thioureido]benzene, 1.2-bis(3-allyloxycarbonyl-2-thioureido)benzene, 1.2-bis[3-(2-propynyloxycarbonyl)-2-thioureido] benzene, 1.2-bis[3-(4-chlorophenoxycarbonyl)-2-thioureido]benzene, 1.2-bis[3-(4-nitrophenoxycarbonyl)-2-thioureido]benzene, 1.2-bis[3-(4-methylphenoxycarbonyl)-2-thioureido]-4-chlorobenzene, 3.4-bis[3-(4-chlorophenoxycarbonyl)-2-thioureido]-toluene, 1.2-bis[3-(2-naphthoxycarbonyl)-2-thioureido]benzene and 1.2-bis[3-(2-naphthoxycarbonyl)-2-thioureido]-4'-nitrobenzene.
 2. A method for the treatment of helminth infections according to claim 1 wherein the benzene derivative is administered orally.
 3. A method for the treatment of helminth infection in domestic animals according to claim 1 in which the benzene derivative is administered orally and wherein the dosage of the benzene derivative is from about 0.1 to 1000 mg. per Kg. of normal body weight. 